The discovery of insulin and its clinical application early in the last century dramatically improved the prospects of people with diabetes. However, the limitations of those initial, unmodified insulin preparations were quickly recognized; most notably, their relatively "short action" meant that multiple daily subcutaneous injections were required. This stimulated a concerted effort to modify the properties of insulin in order to extend the duration of its blood glucose-lowering effect, minimize dosing frequency, and decrease the burden of treatment. The first successful attempts to prolong insulin's action were achieved by modifying its formulation with additives such as protamine and zinc, culminating in the production of "intermediate-acting" neutral protamine Hagedorn (NPH) insulin in the 1940s and the lente family of insulins in the 1950s. However, NPH and lente insulins were still associated with several limitations, including considerable variability of effect and a pronounced peak in their time-action profile. In the 1980s, the focus of research moved toward the modification of insulin itself with the aim of producing a "long-acting" insulin that would better satisfy basal insulin requirements over the entire day. Once-daily insulin glargine was the first "long-acting" insulin analog in clinical practice, followed by once- or twice-daily insulin detemir and, more recently, insulin degludec, which is now being evaluated for administration at less frequent intervals. These analogs demonstrate several benefits over "intermediate-acting" insulins, including a lower risk of both overall hypoglycemia and nocturnal hypoglycemia and reduced day-to-day glucose variability, making it more feasible to achieve better fasting and overall glycemic control. Long-acting insulin analogs (insulin glargine and insulin detemir) are now firmly established as key tools in the battle against diabetes, and ongoing clinical research of insulin-based therapy should focus on treatment strategies to maximize their benefits. To date, the clinical experience with insulin degludec is limited but demonstrates it has comparable efficacy to insulin glargine.